Influence of macrophages and lymphocytes on the survival and axon regeneration of injured retinal ganglion cells in rats from different autoimmune backgrounds

Abstract

The immune response after neural injury influences the survival and regenerative capacity of neurons. In the primary visual pathway, previous studies have described beneficial effects of macrophages and T-cells in promoting neural survival and axonal regeneration in some rat strains. However, the contributions of specific cell populations to these responses have been unclear. In adult Fischer (F344) rats, we confirm prior reports that intravitreal macrophage activation promotes the survival of retinal ganglion cells (RGCs) and greatly enhances axonal regeneration through a peripheral nerve graft. Neonatal thymectomy that results in elimination of T-cell production enhanced RGC survival after axotomy, but diminished the effect of intravitreal macrophage activation on axon regeneration. Thus, in F344 rats, lymphocytes appear to suppress RGC survival but augment the pro-regenerative effects of macrophages. The cytotoxic effect of lymphocytes on RGCs was confirmed in in vitro studies; coculture of retinal explants with lymphocytes led to a 60% reduction in viable RGCs. Similar in vivo results were obtained in Sprague Dawley rats. By comparison, in adult Lewis rats, neither RGC survival nor axonal regeneration was increased after intravitreal macrophage activation. Neonatal thymectomy had only a small beneficial effect on RGC survival, and although Lewis lymphocytes reduced RGC viability in culture, they did so to a lesser extent. Thus, in addition to a complex role of lymphocytes, particularly T-cells, after central nervous system injury, the present results demonstrate that the impact of macrophages is also influenced by genetic background.